DESCRIPTION: The long term goal for this work is to determine the molecular basis of Huntington's disease (HD). The basis for this progressive neurological disorder is an expanded CAG repeat in the Huntington gene that codes for a long polyglutamine repeat (11, 28, 51, 63, 69). The work proposed in this competitive renewal extends work completed during the first 2 years of funding during which the PI made a mouse with a 90 unit CAG repeat in the murine HD homolog (Hdh (CAG) 90). Recent work has shown the presence of Neuronal intranuclear inclusions (NIIs). The PI will also make mice with modifications of Hdh (CAG) 90 designed to enhance access of the polyglutamine-containing portion of the mutant protein to the nucleus. The PI will assess the role these modifications play in the formation of NIIs and the possible role NIIs play in causing abnormalities.